Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: From thymocyte to lymphoblast

Department of Hematology, Cliniques Universitaires St Luc, Catholic University of Louvain, Brussels, Belgium.
Leukemia (Impact Factor: 10.43). 10/2006; 20(9):1496-510. DOI: 10.1038/sj.leu.2404302
Source: PubMed


For long, T-cell acute lymphoblastic leukemia (T-ALL) remained in the shadow of precursor B-ALL because it was more seldom, and showed a normal karyotype in more than 50% of cases. The last decennia, intense research has been carried out on different fronts. On one side, development of normal thymocyte and its regulation mechanisms have been studied in multiple mouse models and subsequently validated. On the other side, molecular cytogenetics (fluorescence in situ hybridization) and mutation analysis revealed cytogenetically cryptic aberrations in almost all cases of T-ALL. Also, expression microarray analysis disclosed gene expression signatures that recapitulate specific stages of thymocyte development. Investigations are still very much actual, fed by the discovery of new genetic aberrations. In this review, we present a summary of the current cytogenetic changes associated with T-ALL. The genes deregulated by translocations or mutations appear to encode proteins that are also implicated in T-cell development, which prompted us to review the 'normal' and 'leukemogenic' functions of these transcription regulators. To conclude, we show that the paradigm of multistep leukemogenesis is very much applicable to T-ALL and that the different genetic insults collaborate to maintain self-renewal capacity, and induce proliferation and differentiation arrest of T-lymphoblasts. They also open perspectives for targeted therapies.

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Available from: Anne Hagemeijer, Mar 17, 2014
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    • "Ras proteins play a critical role in the transmission of survival signals from the cell membrane receptors to the intracellular transduction pathways. Mutations of RAS genes are common and have been described in various malignancies including acute leukemias [2]. They lead to the constitutive activation of the RAS-MAPK signaling cascade. "
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    • "Interestingly, it was found that the MLL gene was overexpressed 2.5-fold in TLFCK when compared to clear cell and chromophobe RCC. MLL is a recurring translocation in hematologic malignancies including lymphoblastic lymphomas and leukemias and can be found in 8% of T-ALL cases [23]. FISH analysis on a formalin fixed paraffin embedded section of tumor from our patient failed to demonstrate translocations or amplifications of the MLL gene. "
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    • "Although activating mutations of NOTCH1 have been detected in 70% of both pediatric and adult T-ALL cases 3,10, significant age-related differences in the frequencies of other genetic alterations have been reported. For example, t(7;10)(q34;q24) and t(10;14)(q24;q11), both of which involve the translocation of the TCR in juxtaposition to the HOX11 transcription factor, occur in 7% of childhood T-ALL cases and 30% of adult T-ALL cases 16. Similarly, a higher prevalence of FBXW7 and PHF6 mutations was reported in adult T-ALL 10,17,18. "
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